Secrets of a double agent: CDK7 in cell-cycle control and transcription

Abstract

In metazoans, cyclin-dependent kinase 7 (CDK7) has essential roles in both the cell-division cycle and transcription, as a CDK-activating kinase (CAK) and as a component of the general transcription factor TFIIH, respectively. Controversy over its double duty has been resolved, but questions remain. First, how does CDK7 achieve the dual substrate specificity necessary to perform both roles? Second, is there a deeper connection implied by the dichotomy of CDK7 function, for example similar mechanisms controlling cell division and gene expression, and/or actual coordination of the two processes? Enzymological studies have revealed solutions to the unusual substrate recognition problem, and there is evidence that the distinct functions of CDK7 can be regulated independently. Finally, despite divergence in their wiring, the CAK-CDK networks of budding yeast, fission yeast and metazoans all link transcriptional regulation with operation of the cell-cycle machinery. This connection might help to ensure that mRNAs encoding effectors of cell division are expressed at the right time in the cycle.

Retinoid-suppressed phosphorylation of RARα mediates the differentiation pathway of osteosarcoma cells

“…Inhibition of CAK phosphorylation of the retinoblastoma tumorsuppressor protein leads cells to exit the cell-cycle G 1 phase (Wu et al, 2001). On the other hand, TFIIH-containing CAK mediates transcription initiation by phosphorylating the largest subunit of RNA polymerase II (Nigg, 1996;Fisher, 2005). These studies suggest that changes in CAK phosphorylation of different substrates modulate cell-cycle G 1 exit and transcriptional control.…”

“…The S77 of RARa (RARaS77) is the main residue phosphorylated by CAK . CAK exists in cells as free CAK or as part of the general transcription factor IIH (TFIIH) complex (Nigg, 1996;Fisher, 2005). Free CAK regulates cell-cycle G 1 progression by phosphorylation activation of CDKs (Nigg, 1996).…”

Developmental expression of Cyclin H and Cdk7 in zebrafish: the essential role of Cyclin H during early embryo development

“…Recent research has identified two non-overlapping sets of Cdks in metazoans: Cdk1, Cdk2, Cdk4 and Cdk6, dedicated to cell-division control, and Cdk8 and Cdk9, primarily implicated in transcription [26]. However, the Cdk7 complex cannot be easily classified [26] as Cdk7/Cyclin H has a dual role: first, as the CAK of cell cycle Cdks, and second, as a component of the general transcription factor TFIIH, phosphorylating the CTD of RNA polymerase II.…”

“…However, the Cdk7 complex cannot be easily classified [26] as Cdk7/Cyclin H has a dual role: first, as the CAK of cell cycle Cdks, and second, as a component of the general transcription factor TFIIH, phosphorylating the CTD of RNA polymerase II.…”

“…These defects may have resulted from cell death in tissues where higher Cyclin H expression levels were observed. To investigate if the above phenotype was caused by the disturbance of initiation of zygotic transcription owing to the fact that Cdk7/Cyclin H functions as components of the general transcription factor TFIIH [26], we tested the expression of boz and ntl in Cyclin H DN mRNA-injected embryos after allowing them to develop to the sphere stage and shield stage, respectively. We found that the expression of boz and ntl was reduced and their normal restricted expression pattern was disrupted ( Figure 9A-D).…”